Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders

Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. We generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid (CSF), and plasma), by profiling thousands of proteins from participants with and without Alzheimer disease (AD). We identified 274, 127, and 32 protein quantitative trait loci (pQTLs) for CSF, plasma, and brain, respectively. Cis-pQTLs were more likely to be tissue-shared, but trans-pQTLs tended to be tissue-specific. Between 48.0 to 76.6% of pQTLs did not colocalize with expression, splicing, DNA-methylation, or histone-acetylation QTLs. Using Mendelian randomization (MR), we nominated proteins implicated in neurological diseases, including AD, Parkinson’s disease or stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies (GWAS) onto functional genes, to discover pathways, and to identify drug targets for neurological diseases.